The Synthesis Of A Novel Carbapenem Antibiotic: Doirpenem

Doripenem,(1R,5S,6S)-2-[(3S,5S)-5-(N-sulfamonylaminomethyl)–pyrrolidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid developed by SHIONOGI&Co., Ltd, is a novel1β-methylcarbapenem antibiotic with the replancement of a sulfamoylaminomethylsubstituted pyrrolidylthio group at C-2position. October2007the U.S. FDA approved the drug injectionfor the clinical treatment of the complexity of intra-abdominal infections that causes by the bacteria andthe complexity of urinary tract infection that causes by variety of bacteria. Doripenem is broad andpotent antibacterial, as the outstanding one in the family of1β-methylcarbapenem, it is attratting more andmore chemists, biologists and pharmanceutists.This process is based on summarize the synthetic process of literature and combining the domesticpharmaceutical intermediates industry status, using commercial (L)-4-hydroxyl proline as starting materialthrough nine steps: protect amidogen, carboxyl and hydroxyl group, reduction by NaBH3, S_N2substitutionand the Mitsunobu reaction to get the side chain. After condensation with mother nucleus:(1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-benzene oxygen adjacent usions oxygen radicals-1-methyl-1-carbongeneration-2-the mold ene-3-carboxylic acid and deprotection by Pd/C, we got ultimate production-doripenem.The structure of doripenem has been verified by¹H-NMR,¹³C-NMR and LC-MS, key intermediateshas been verified by HPLC, LC-MS,¹H-NMR.Previous protecting groups of the preparation of the side chain of doripenem reported in the literatureare p-nitrobenzyloxycarbonyl (PNZ), p-methyloxybenzylcarbonyl (PMZ), t-butoxycarbonyl (Boc), andPNZ is the best. After the condensation with commercial mother nucleus and the side chain whichsynthesized by ourselves, we finished the synthesis of a novel1β-methylcarbapenem antibiotic: Doripenem.In consideration of the actual situation of industrialization, we not only finish the synthesis with PNZprotective group, but also explore the synthsis with CBz protective group. Compared to PNZ group,protective group-CBz has the advantage of low prices, avoid disadvantages of separation caused byp-Toluidine in the step of deprotection and cut steps, extension new better routes. In the experimentalprocess during the two routes, we optimise each of them according to the characteristics of their intermediates. The procedure is cheap, simple and suitable for industry. Specific improvement path asfollows:a) Protection of the amino reaction： choose potash, and approved the right dosage for chosen aoptimal pH value.b) methylsulfonyl reaction: useing CBz instead of PNZ as protecting groups to avoid the solutionbecome viscous, and also save a lot of time for mixing disperse.c) Sodium borohydride reaction: use THF-EtOH as solvent, can greatly short the reaction time.d) S_N2reaction: use nitrogen protection can improve the purity of the product,and also make thecolor slighter.e) Mitsunobu reaction: Anhydrous ethyl acetate, can improve the purity of side chain,and increaseyield. DIAD instead of the DEAD have the same yield and cost lower.f) In the condensation step: Replacement of the solvent, to avoid the residue of the original solventDMF;elevated the reaction temperature to make it easy to control; Serious emulsification due tothe extraction, therefore, we eliminating the need for this operation and join the poor solvent toprecipitate the product directly; The purity of the product is high enough to eliminating the needfor recrystallizationg) The catalytic hydrogenation: post-processing without salt and layered with ethyl acetate, canget more water phase, then directly freeze-dried solids.